Identification of potent, selective, and metabolically stable peptide antagonists to the calcitonin gene-related peptide (CGRP) receptor

J Med Chem. 2008 Dec 25;51(24):7889-97. doi: 10.1021/jm8009298.


Calcitonin gene-related peptide (CGRP) is a 37-residue neuropeptide that can be converted to a CGRP(1) receptor antagonist by the truncation of its first seven residues. CGRP(8-37), 1, has a CGRP(1) receptor K(i) = 3.2 nM but is rapidly degraded in human plasma (t(1/2) = 20 min). As part of an effort to identify a prolonged in vivo circulating CGRP peptide antagonist, we found that the substitution of multiple residues in the CGRP peptide increased CGRP(1) receptor affinity >50-fold. Ac-Trp-[Arg(24),Lys(25),Asp(31),Pro(34),Phe(35)]CGRP(8-37)-NH(2), 5 (K(i) = 0.06 nM) had the highest CGRP(1) receptor affinity. Using complimentary in vitro and in vivo metabolic studies, we iteratively identified degradation sites and prepared high affinity analogues with significantly improved plasma stability. Ac-Trp-[Cit(11,18),hArg(24),Lys(25),2-Nal(27,37),Asp(31),Oic(29,34),Phe(35)]CGRP(8-37)-NH(2), 32 (K(i) = 3.3 nM), had significantly increased (>100-fold) stability over 1 or 5, with a cynomolgus monkey and human in vitro plasma half-life of 38 and 68 h, respectively.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Calcitonin Gene-Related Peptide Receptor Antagonists*
  • Chemistry, Pharmaceutical / methods*
  • Cricetinae
  • Cricetulus
  • Drug Design
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Macaca fascicularis
  • Male
  • Molecular Conformation
  • Molecular Sequence Data
  • Protein Binding
  • Receptors, Calcitonin Gene-Related Peptide / chemistry*


  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Receptors, Calcitonin Gene-Related Peptide